European Medicines Agency Workshop on Antibacterials, London 7-8 February 2011

Consideration of some other specific indications: Bacteremia

Harald SeifertInstitut für Medizinische Mikrobiologie, Immunologie und Hygiene der

Universität zu Köln

Bacteremia (Bacteræmia in British English, also known as ‘blood poisoning’ or ‘toxemia’) is the presence of viable bacteria in the blood.

Bacteremia is most commonly diagnosed by blood culture.

From Wikipedia, the free encyclopedia

Definitions: Bacteremia

True bacteremia = clinically significant

Contamination = clinically not significant

Pseudobacteremia = systematic contamination

Transient, intermittent, or persistent bacteremia

Definitions: Bacteremia

Bacteremia is a microbiologic

finding, it is not an infection per se

Bacteremia with at least one positive blood culture +

clinical manifestations of infection (such as fever, chills and/or hypotension)

clinically always significant

CDC Definitions: Bloodstream infectionClinical definition

Laboratory-confirmed bloodstream infection mustmeet at least one of the following criteria:

Criterion 1: Patient has a recognized pathogen culturedfrom one or more blood culturesand organism cultured from blood is not related to aninfection at another site.

CDC Definitions: Primary bloodstream infection

Horan TC, Gaynes RP. Surveillance of nosocomial infections. In: Hospital Epidemiology and Infection Control, 3rd ed., Mayhall CG, editor. Philadelphia: Lippincott Williams & Wilkins, 2004:1659-1702.

Criterion 2: Patient has at least one of the following signs orsymptoms: fever (38°C), chills, or hypotensionand at least one of the following:a. Common skin contaminant (e.g., diphtheroids, Bacillus sp., Propionibacterium sp., coagulase-negative staphylococci, ormicrococci) is cultured from two or more blood culturesdrawn on separate occasionsb. Common skin contaminant is cultured from at least one bloodculture from a patient with an intravascular line, and the physicianinstitutes appropriate antimicrobial therapyand signs and symptoms and positive laboratory results are notrelated to an infection at another site.

CDC Definitions: Primary bloodstream infection

Central Line-Associated Bloodstream Infection (CLABSI) Primary laboratory confirmed bloodstream infection that iscentral line-associated (i.e., a central catheter was in place at the time of, or within 48 hours before, onset of the event).

Definition is used for infection-control surveillancepurposes, no microbiological proof required.

CDC Definitions: CLABSI and CR-BSI

O’Grady NP et al. Guidelines for the prevention of intravascular catheter-relatedinfections. Am J Infect Control. 2002; 30:476-89.Mermel L, et al. Clinical Practice Guidelines for the Diagnosis and Management of Intravascular Catheter-Related Infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis 2009; 49:1–45

Catheter-Related Bloodstream Infection (CR-BSI) Bacteremia or fungemia in a patient who has an intravascular device and ≥1 positive blood culture result obtained from the peripheral vein, clinical manifestations of infection (e.g., fever, chills, and/or hypotension), and no apparent source for BSI except the catheter.

One of the following should be present (as microbiological proof): (i) positive result of semiquantitative (>15 cfu per catheter segment) or quantitative (>102 cfu per catheter segment) catheter culture, whereby the same organism (species) is isolated from a catheter segment and a peripheral blood culture;(ii) simultaneous quantitative cultures of blood with a ratio of > 3:1 cfu/mL of blood (catheter vs. peripheral blood); (iii) differential time to positivity >2h (catheter vs. peripheral blood)

CDC Definitions: CLABSI and CR-BSI

Laboratory-confirmed bloodstream infection mustmeet at least one of the following criteria:

Criterion 1: Patient has a recognized pathogen culturedfrom one or more blood culturesand organism cultured from blood is related to aninfection at another site.

CDC Definitions: Secondary bloodstream infection

Horan TC, Gaynes RP. Surveillance of nosocomial infections. In: Hospital Epidemiology and Infection Control, 3rd ed., Mayhall CG, editor. Philadelphia: Lippincott Williams & Wilkins, 2004:1659-1702.

Sources of nococomial bloodstream infectionsCologne, 1997/1998 (n=322)

Primary BSI Secondary BSI

n = 252

n = 70 (21.7%)

Sourceundetermined

n=120

CR-BSIn=132

Other (10)Cardiovascular (6)Pneumonia (11)

Urinary tract (14)

Gastrointestinal tract (14)

Skin and skin structures (15)

41.0%

37.3%

Unpublished data

S. aureus bloodstream infection (SAB):source of infection

other; 12% endocarditis; 10%

skin/soft tissue; 7%

post-OP; 5%

vertebral osteomyelitis; 5%

pneumonia; 3%

pacemaker; 1%unknown; 25%

catheter-related; 32%

N=417, January 2006 – December 2008

Daptomycin (Cubicin) is approved in the U.S. and in Europe, at 6 mg/kg, for the treatment of S. aureus bloodstream infections, including right-sided IE caused by MRSA and MSSA.

Cubicin is the only I.V. antibiotic approved for this indication based on results of a prospective, randomized, controlled registration trial.

Study design:

Open-label, randomized trial conducted between August 2002 and February, 2005.

Eligible patients were ≥ 18 y of age and had ≥ 1 blood cultures positive for S. aureus within two days before initiating study medication.

Patients were ineligible if they had a creatinine clearance of ≤ 30 ml/min, osteomyelitis, polymicrobial bacteremia, or pneumonia.

Fowler V et al. N Engl J Med 2006;355:653-65.

Daptomycin vs. standard therapy for bacteremiaand endocarditis caused by S. aureus

Clinical outomes:

The primary outcome was the clinical success rate in each of thetwo treatment groups in the MITT population at the visit 42 daysafter the end of therapy. Non-inferiority margin: 20%

Failure at this visit was defined as clinical failure, microbiologic failure, death, failure to obtain blood culture, receipt of potentially effective non-study antibiotics, or premature discontinuation of the study medication because of clinical failure, microbiologic failure, or an adverse event.

Fowler V et al. N Engl J Med 2006;355:653-65.

Daptomycin vs. standard therapy for bacteremiaand endocarditis caused by S. aureus

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• Drug class: Cephalosporin (with anti-MRSA activity)

• Approval: FDA 29.10.2010

• Indications: Community-acquired pneumonia; cSSST

• Dosing: 600mg IV bid

Ceftarolin (Teflaro, Forest Laboratories)

Clinical studies• FOCUS I and FOCUS II studied adult patients who were

hospitalized with moderate to severe CAP (PORT III-IV);Ceftaroline 600mg iv bid vs. ceftriaxone1g iv od

• Exlusion: CAP suitable for outpatient tx with an oral agent• Clinical cure in the MITT population: 82.6% vs 76.6%• Bacteremia rate 3.5% (43/1225 patients included)• Death-rate 2.2% (27 of 1225 patients included)

Ceftaroline (Teflaro, Forest Laboratories)

File TM et al. Integrated Analysis of FOCUS 1 and FOCUS 2: Randomized, Doubled-Blinded, Multicenter Phase 3 Trials of the Efficacy and Safety of Ceftaroline Fosamil versus Ceftriaxone in Patients with Community-Acquired Pneumonia. Clin Infect Dis 2010; 51:1395–1405

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Clinical studies• The CANVAS I and CANVAS II trials evaluated ceftaroline

monotherapy (600mg iv bid) versus vancomycin plus aztreonam (each, 1g iv bid) in adult patients with complicated skin and skin structure infections (cSSSI)

• Clinical cure in the MITT population: 85.9% vs 85.5%• Bacteremia rate 4.0% (55/1378 patients included)• Death-rate 0.2% (3/1378 patients, none related to cSSSI)

Ceftaroline (Teflaro, Forest Laboratories)

Corey GR et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis. 2010;51:641-50.

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What ceftaroline dosage would you use if you had to treat a patient with a serious infection?

Do we need new drugs such as ceftaroline for CAP and cSSSI?

We need new drugs for serious and life-threatening infections.

We need clinical studies in patients with serious infections such as

patients with BSI.

We need to know what dose to be used to treat these patients.

Ceftaroline (Teflaro, Forest Laboratories)